Process for the preparation of substituted carboxylic esters

ABSTRACT

A process for the preparation of 2(S)-alkyl- 5 -halogenpent-4-ene carboxylic esters by enzymatic hydrolysis, comprising the steps: a) enzymatic hydrolysis of racemic 2-alkyl-5-halogenpent-4-ene carboxylic esters in aqueous and alkaline medium in the presence of an esterase; b) isolation of 2(S)alkyl-5-halogenpent-4-ene carboxylic esters by extraction with an organic solvent; c) isolation of 2(R)-alkyl-5-halogenpent- 4 -ene carboxylic acids from the aqueous-alkaline medium; d) Esterification of 2(R)-alkyl-5-halogenpent-4-ene carboxylic acids, e) subsequent racemization to form 2-alkyl-5-halogenpent-4-ene carboxylic esters; and f) return of the racemate obtained in step e) to step a), if necessary together with fresh racemic 2-alkyl-5-halogenpent-4-ene carboxylic esters. The process permits the undesired R-stereoisomers to be converted into the desired 2(S)-alkyl-5-halogenpent-4-ene carboxylic esters to avoid waste product from the synthesis.

[0001] The invention relates to the preparation of2(S)-alkyl-5-halogenpent-4-ene carboxylic esters, in which the2(S)-stereoisomer is obtained by enzymatic hydrolysis of the racemate,followed by esterification then racemization of the resulting2(R)-alkyl-5-halogenpent-4-ene carboxylic acid, and returning theresulting racemic 2-alkyl-5-halogenpent-4-ene carboxylic ester to theprocess.

[0002] In EP-A-0 678 503, δ-amino-γ-hydroxy-α-aryl-alkanecarboxamidesare described, which exhibit renin-inhibiting properties and could beused as antihypertensive agents in pharmaceutical preparations.

[0003] In WO 01/09079, a multistep manufacturing process is described,in which the central intermediate is a2,7-dialkyl-8-aryl-4-octenoylamide of formula A

[0004] and in particular of formula A1,

[0005] wherein R₁ and R₂ independently of one another are H, C₁-C₆alkyl,C₁-C₆halogenalkyl, C₁-C₆alkoxy, C₁-C₆alkoxy-C₁-C₆alkyl, orC₁-C₆alkoxy-C₁-C₆alkyloxy, R₃ is C₁-C₆alkyl, R₄ is C₁-C₆alkyl, R₆ isC₁-C₆alkyl, R₅ is C₁-C₆alkyl or C₁-C₆alkoxy, or R₅ and R₆ together aretetramethylene, pentamethylene, 3-oxa-1,5-pentylene or —CH₂CH₂O—C(O)—substituted if necessary with C₁-C₄alkyl, phenyl or benzyl.

[0006] The compounds of formulae A and A1 are obtainable by reacting acompound of formula B

[0007] as racemate or enantiomer, with a compound of formula C, asracemate or enantiomer,

[0008] wherein R₁ to R₄, R₅ and R₆ are as defined above, Y is Cl, Br orI and Z is Cl, Br or I, in the presence of an alkali metal or alkalineearth metal. Y and Z are preferably Br and especially Cl.

[0009] In WO 01/09083, the compounds of formula C as racemates and2(S)-stereoisomers are described as well as their preparation. Thestereoisomers are obtained by hydrolysis of corresponding racemiccarboxylic esters to form their carboxylic acids, followed by racemateseparation by means of salt formation with chiral amine bases andcrystallization. A stereoselective synthesis is further described forthe preparation of 2(S)-pentene carboxylic acids and theirderivatization to form the corresponding pentene carboxylic acidhalides, esters and amides. This stereoselective synthesis of the estersis not yet satisfactory and is regarded as too costly.

[0010] The racemic compounds of formula D

[0011] are prepared as described in WO 01/09083 by coupling of3-alkylbutane carboxylic esters withtrans-1-halogenmethyl-2-halogenethylene. Isolation of the2(S)-alkyl-5-halogenpent-4-ene carboxylic ester is not described, butonly the possibility is disclosed of performing a racemate resolution ofthe carboxylic esters obtained in the synthesis by means of esterases,in which the very stable 2(R)-alkyl-5-halogenpent-4-ene carboxylic acidis then formed as a by-product. It is extremely desirable to convert theentire racemate directly into the 2(S)-carboxylic ester of formula D,especially since these carboxylic esters may be used in a newstereoselective synthesis for the preparation of a central intermediateof formula A2

[0012] directly instead of the compound of formula C according to theabove coupling reaction. These carboxylic esters may of course also beconverted to the 2(S)-carboxylic amides of formula C for use in theabove coupling reaction.

[0013] However, a fundamental disadvantage of racemate resolutionremains. Not more than 50% of the desired stereoisomer is obtainable.The 2(R)-stereoisomer must be disposed of together with processinglosses arising from the racemate resolution. These large quantities makeracemate resolution completely uneconomical. A more effective method istherefore needed in which, above all, the occurrence of these largewaste disposal quantities is reduced or prevented.

[0014] It has now been surprisingly found that, in the preparation of2(S)-alkyl-5-halogenpent-4-ene carboxylic esters, the occurrence oflarge quantities of waste products can be avoided and even that onlyvery minor losses have to be expected using enzymatic racemateresolution, if the 2(R)-alkyl-5-halogenpent-4-ene carboxylic acid formedby enzymatic hydrolysis is isolated and returned to the separationprocess. The recycling ensures overall an extremely economical process,since the total yields are high and only unavoidable processing losseshave to be expected. The recycling also offers outstanding ecologicaladvantages, because the formation of waste products overall is reducedto a minimum, and a costly disposal of large quantities of synthesisproducts can be avoided.

[0015] The object of the invention is a process for the preparation of2(S)-alkyl-5-halogenpent-4-ene carboxylic esters by enzymatichydrolysis, comprising the steps

[0016] a) enzymatic hydrolysis of racemic 2-alkyl-5-halogenpent-4-enecarboxylic esters in aqueous and alkaline medium in the presence of anesterase;

[0017] b) isolation of 2(S)-alkyl-5-halogenpent-4-ene carboxylic estersby extraction with an organic solvent;

[0018] c) isolation of 2(R)-alkyl-5-halogenpent-4-ene carboxylic acidsfrom the aqueous-alkaline medium;

[0019] d) Esterification of 2(R)-alkyl-5-halogenpent-4-ene carboxylicacids,

[0020] e) subsequent racemization to form 2-alkyl-5-halogenpent-4-enecarboxylic esters; and

[0021] f) return of the racemate obtained in step e) to step a), ifnecessary together with fresh racemic 2-alkyl-5-halogenpent-4-enecarboxylic esters.

[0022] The 2(S)-alkyl-5-halogenpent-4-ene carboxylic esters maycorrespond to formula I,

[0023] wherein

[0024] R₁ is C₁-C₆alkyl, Z is chlorine, bromine or iodine, and the ORgroup forms an ester group with the carbonyl residue.

[0025] The racemate may correspond to formula II,

[0026] wherein

[0027] R₁ is C₁-C₆alkyl, Z is chlorine, bromine or iodine, and the ORgroup forms an ester group with the carbonyl residue.

[0028] The 2(S)-alkyl-5-halogenpent-4-ene carboxylic acid may correspondto formula III,

[0029] wherein

[0030] R₁ is C₁-C₆alkyl, and Z is chlorine, bromine or iodine.

[0031] R₁ is preferably C₁-C₄alkyl. Examples of alkyl are methyl, ethyl,n- and i-propyl, n-, i- and t-butyl, pentyl and hexyl. It is veryparticularly preferred when R₄ is i-propyl.

[0032] It is especially preferred when Z is Cl.

[0033] In the ester group, R is preferably an organic group with 1 to18, preferably 1 to 12, and especially preferably 1 to 8 C-atoms and ifnecessary comprises heteroatoms selected from group O and N.

[0034] R may be a branched and preferably linear alkyl, which preferablycomprises 1 to 18, especially preferably 1 to 12, and—with particularpreference—1 to 6 C atoms. Some examples are methyl, ethyl, n-propyl,n-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl,teradecyl, hexadecyl and octadecyl. Especially preferred are methyl andethyl. The alkyl may be substituted, for example with C₁-C₄alkoxy, suchas methoxy or ethoxy. Examples of substituted alkyl are methoxyethyl andethoxyethyl.

[0035] R may be cycloalkyl with 3 to 8, and preferably 5 or 6ring-carbon atoms. Examples are cyclopropyl, cyclobutyl, cyclohexyl,cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. The cycloalkyl maybe substituted with C₁-C₄alkyl or C₁-C₄alkoxy.

[0036] R may be cycloalkyl-C₁-C₄alkyl with 3 to 8, and preferably 5 or 6ring-carbon atoms, which is unsubstituted or substituted with C₁-C₄alkylor C₁-C₄alkoxy. Examples are cyclopentylmethyl, cyclohexylmethyl,methylcyclohexylmethyl and cyclohexylethyl.

[0037] R may be C₆-C₁₀aryl which is unsubstituted or substituted withC₁-C₄alkyl or C₁-C₄alkoxy. Examples are phenyl, naphthyl, methylphenyl,ethylphenyl and i-propylphenyl.

[0038] R may be C₆-C₁₀aryl-C₁-C₄alkyl which is unsubstituted orsubstituted with C₁-C₄alkyl or C₁-C₄alkoxy. Examples are benzyl,methylbenzyl and phenylethyl.

[0039] Especially preferred compounds of formulae I, II and III arethose wherein Z is chlorine, R₁ is C₁-C₄alkyl and especially preferablyi-propyl. In compounds of formulae I and II, R is preferably C₁-C₄alkyl.

[0040] A quite especially preferred embodiment comprises compounds offormulae I, II and III wherein Z is chlorine and R₁ is i-propyl, as wellas compounds of formulae I and II wherein R is methyl or ethyl.

[0041] Particularly preferred are compounds of formulae I and II whereinZ is chlorine, R₁ is i-propyl, and R is methyl or ethyl.

[0042] Process step a)

[0043] The enzymatic hydrolysis of racemic carboxylic esters is knownper se and familiar to a person skilled in the art. On hydrolysis, theproperty of the stereospecific hydrolysis of esterases is exploited tohydrolyse only specific enantiomers by catalytic conversion. Theseesterases are known and commercially available. The esterases aregenerally used in catalytic quantities, for example 0.001 to 10 andpreferably 0.01 to 5 percent by weight, related to the carboxylic acid.The reaction is carried out in aqueous medium, in which the presence ofpH buffers that can keep the pH value constant is favourable. It isexpedient to adjust the pH value to slightly alkaline, for example inthe range more than 7 to 10, preferably 7.5 to 9. The aqueous medium maycontain organic solvents miscible with water, especially alcohols suchas methanol, ethanol, n- or i-propanol and butanol. Many buffer agentsare known; phosphate buffers are especially suitable. The process may becarried out at slightly elevated reaction temperatures, for example fromroom temperature to 60° C. It is expedient to conduct the hydrolysisusing diluted bases of alkali metals and alkaline earth metals,especially sodium or potassium hydroxide. The consumption of hydroxidescan be followed and the endpoint of the reaction thus determined.Aqueous hydroxide solutions may be added altogether or in portions, forexample drop by drop.

[0044] Process Step b)

[0045] To isolate the non-hydrolysed carboxylic esters of formula I, aninert organic solvent or solvent mixture which dissolves the ester andis not miscible with water, and which can therefore be readily separatedthrough the formation of a two-phase system, is added to the reactionmixture. Suitable solvents are hydrocarbons (pentane, hexane,cyclohexane, methyl cyclohexane, benzene, toluene and xylene),halogenated hydrocarbons (methylene chloride, chloroform,tetrachloroethane), ketones (acetone, methyl isobutyl ketone), andethers (diethyl ether, di-n-propyl ether, dibutyl ether, i-propyl methylether, t-butyl methyl ether, ethylene glycol dimethyl ether,tetrahydrofuran and dioxan). Compounds of formula I may be isolated fromthe separated organic phase in the customary manner, for example bywashing and drying the organic phase, distilling off the used solventand if necessary purifying the resulting product by distillation. Thecarboxylic esters of formula I are obtained in almost theoretical yieldwith an enantiomeric purity of more than 99%.

[0046] Process Step c)

[0047] 2(R)-Alkyl-5-halogenpent-4-ene carboxylic acids may be isolatedfrom aqueous-alkaline medium in a manner known per se, for example byprecipitating the acid or salts in a suitable medium, or preferably byextraction of the carboxylic acids. To this end, the basic reactionresidue is first acidified, for example with mineral acids such assulfuric acid or hydrochloric acid. An inert organic solvent or solventmixture is then added which dissolves the acid and is not miscible withwater and can therefore be readily separated by the formation of atwo-phase system. Suitable solvents are polar organic solvents, inparticular ether. After extraction, the organic phases can be washed anddried. The solvent is then removed, for example by distillation, ifnecessary in a vacuum. The residue remaining after removal of thesolvent can be used without further purification in in the next step d).2(R)-Alkyl-5-halogenpent-4-ene carboxylic acids are obtained in analmost quantitative yield.

[0048] Process Step d)

[0049] Esterification methods for carboxylic acids are generally known.For example, the esterification may be carried out with alcohols in thepresence of mineral acids such as hydrochloric acid or sulfuric acid,the addition of water-binding agents or azeotropic removal of thereaction water being advantageous. It is more expedient to useesterification agents such as diazoalkanes, dialkyl sulfates or acetals,especially activated acetals such as N,N-dimethylaminoformamide dialkylacetals, which may be used alone or together with appropriate alkalimetal alcoholates. The reaction may be performed without or in thepresence of inert solvents. The reaction is carried out at an elevatedtemperature, for example 40 to 150° C., preferably 50 to 100° C.

[0050] The carboxylic acids obtained in process step c) may bederivatized before esterification, for example to form acyl halides, inparticular chlorides and bromides. Halogenation reagents are known.Inorganic halides such as phosphorus pentachloride or thionyl chlorideare frequently used. The acyl halides may be esterified in a mannerknown per se by reaction with alcohols either without or in the presenceof a solvent. The esterification method is exothermic, and cooling ofthe reaction is advantageous at the start of the reaction. The reactionis then performed at an elevated temperature, for example 40 to 150° C.,and preferably 50 to 100° C.

[0051] Process Step e)

[0052] The (R)-carboxylic ester obtained in process step d) does notneed to be isolated for racemization. It is advantageous to perform theracemization in the same reaction vessel following esterification.Methods of racemization are known per se, for example heating to hightemperatures and/or adding strong bases. Preferably alkali metalalcoholates are used as bases, especially sodium or potassiumalcoholates. When selecting the alcohol for the alcoholate, it isexpedient to ensure that it corresponds to the alcohol in the estergroup of the (R)-carboxylic ester. If a (R)-carboxylic acid methyl esteris prepared, it is advantageous to use sodium or potassium methylate.The alcoholate may be used in catalytic to equimolar quantities, forexample 0.01 to 1 mol, in relation to the (R)-carboxylic ester. If theesterification is carried out with an alkali metal alcoholate via anacyl halide, the quantity of alkali metal alcoholate determined forracemization may already be added during esterification. In this case,racemization may already start to occur during esterification. Thereaction temperature may range for example from 40 to 150° C. andpreferably from 50 to 100° C. Under the specified conditions, completeracemization is achieved.

[0053] The process for isolation of the racemic carboxylic ester may becarried out in a manner known per se. It is advantageous to useextraction methods, as described earlier. The carboxylic esters areobtained in yields of 97% or more, the (R)-carboxylic acid of processstep c) being quantitatively converted to the corresponding racemiccarboxylic ester. Racemization and esterification are performedconsecutively in the same reaction vessel, which offers processengineering advantages.

[0054] Process Step f)

[0055] The residue obtained after removal of the solvent may beimmediately reused as crude product in process step a). Using theprocess according to the invention, the desired (S)-carboxylic esterscan be prepared with very high yields and a high degree of chemical andoptical purity, and the undesired (R)-carboxylic acid which inevitablyoccurs in the separation process can be converted to the desired(S)-carboxylic esters. Complete utilization of the synthesized racemic2-alkyl-5-halogenpent-4-ene carboxylic ester is thereby achieved, anddisposal of the undesired waste product of synthesis,(R)-2-alkyl-5-halogenpent-4-ene carboxylic acid, can be completelyavoided.

[0056] The following examples explain the invention in more detail.

[0057] A) Synthesis of Racemic 2-alkyl-5-halogenpent-4-ene CarboxylicEsters

[0058] Example A1: Synthesis of

[0059] An agitated solution of 271.3 ml diisopropylamine and 1.6 ltert-butyl methyl ether is cooled to −10° C., and 768 ml 2.5 M n-hexyllithium solution (in hexane) is added over a period of 15 minutes. Thesolution is stirred for 5 minutes at −10° C., and then 211.2 ml methylisovalerate is added drop by drop over a period of 10 minutes. Thesolution is stirred for 15 minutes, and then 179.6 g potassiumtert-butylate in 260 ml 1,2-dimethoxyethane is added over a period of 15minutes at −10° C. The reaction mixture is stirred for 1 h at −5° C.,and then 195.3 g trans-1,3-dichloropropene is added drop by drop. Thereaction mixture is stirred for a further 3 hours at −5° C., and then600 ml aqueous 10 N HCl is added at 0° C. The organic phase is separatedoff and the aqueous phase extracted with tert-butyl methyl ether (2×0.5I). The organic phases are washed consecutively with 1N HCl (0.5 I) andaqueous NaCl solution, dried with sodium sulfate and concentrated byevaporation. By means of distillation, title compound A is obtained fromthe residue as a colourless oil (249.1 g, 79%). ¹H-NMR (300 MHz, CDCl₃,δ): 0.95 (m, 6H), 1.90 (m, 1H), 2.10-2.20 (m, 3H), 3.35 (s, 3H),5.80-6.0 (m, 2H) ppm.

[0060] B) Preparation of (S)-2-alkyl-5-halogenpent-4-ene CarboxylicEsters

[0061] Example B1: Preparation of

[0062] A solution of 225 g A in 94 ml isopropanol is added to 2.35 lphosphate buffer (pH 7.0). In the presence of 9.42 ml (20700 U) pigliver esterase (Technical Grade, Roche Diagnostics), the mixture isagitated at pH 8.0 and 40° C. until consumption of 623 ml 1.0 N NaOH.The reaction mixture is mixed with tert-butyl methyl ether at roomtemperature and filtered via Hyflo®. The organic phase is separated offand the aqueous phase extracted with tert-butyl methyl ether (2×1 I).The organic phases are washed consecutively with 5% aqueous Na₂CO₃solution (3×0.7 I) and concentrated saline (1×1 l), dried with 300 gNa₂SO₄, concentrated by evaporation and dried in a vacuum. By means ofdistillation, title compound B is obtained from the residue as acolourless oil (107.7 g, 47%) with an ee greater than 99%. ¹H-NMR (300MHz, CDCl₃, δ): 0.95 (m, 6H), 1.90 (m, 1H), 2.10-2.20 (m, 3H), 3.35 (s,3H), 5.80-6.0 (m, 2H) ppm.

[0063] C) Isolation of (R)-2-alkyl-5-halogenpent-4-ene Carboxylic Acids

[0064] Example C1: Preparation of

[0065] The alkaline aqueous phases obtained and combined as describedunder example B1 are acidified at 0° C. with 4N HCl (1 I) and extractedwith tert. butyl methyl ether (3×0.7 l). The organic phases are washedwith water (0.5 l) and aqueous NaCl solution, dried over sodium sulfateand concentrated on a rotary evaporator. The residue (126 g) correspondsto title compound C, which is used as crude product in examples D1 andD2.

[0066] D) Racemization to 2-alkyl-5-halogenpent-4-ene Carboxylic Esters

[0067] Example D1: Preparation of A, esterification withN,N-dimethylformamide dimethyl acetal 106 g C (crude) is heated whilestirring to 70° C. 136 ml N,N-Dimethylformamide dimethyl acetal is addeddrop by drop over a period of 30 minutes at 65-70° C. and stirred underreflux for a further 2 hours. 55.6 ml sodium methylate (5.4 M inmethanol) is added drop by drop over a period of 5 minutes at refluxtemperature and stirred under reflux for a further 2 hours. The reactionsolution is cooled to room temperature, poured onto 1 l water andextracted with tert-butyl methyl ether (2×0.5 l). The organic phases arewashed with water/aqueous NaCl solution (9:1; 1 l), dried over sodiumsulfate and concentrated on a rotary evaporator.

[0068] The residue 110.7 g (97%) corresponds to compound A. Completeracemization is demonstrated by gas chromatography (Lipodex® E,Macherey-Nagel).

[0069] Example D2: Preparation of A via acyl chloride

[0070] 106 g C (crude) is heated while stirring to 60° C. 87.3 mlthionyl chloride is added drop by drop over a period of 30 minutes at60-70° C. (gas evolution) and stirred for a further 60 minutes at 70° C.The thionyl chloride excess is distilled off under a slight vacuum(300-30 mbar) and the residue obtained is cooled to 0° C. 60 ml methanolis then added drop by drop at 0 to not more than 8° C. over a period of10 minutes. 222 ml sodium methylate (5.4 M in methanol) is added drop bydrop at 8-12° C. (exothermic reaction) over a period of 20 minutes. Thereaction mixture is heated to reflux and agitated for a further 7 hours.The reaction solution is cooled to room temperature, poured onto icewater (1 l) and extracted with tert-butyl methyl ether (2×0.5 l). Theorganic phases are washed with water/aqueous NaCl solution (9:1; 1 l),dried over sodium sulfate and concentrated on a rotary evaporator. Theresidue 111.2 g (97%) corresponds to title compound A. Completeracemization is demonstrated by gas chromatography (Lipodex® E,Macherey-Nagel).

[0071] E) Recycling of Compounds A

[0072] Example E1:

[0073] The compound A prepared according to example D1 is subjected toracemate resolution with 115 g fresh compound A as described in exampleB1. The same separation result is obtained. The recycling as describedin examples C1 and D1 may then be continued.

[0074] Example E2:

[0075] The compound A prepared according to example D2 is subjected toracemate resolution with 114 g fresh compound A as described in exampleB1. The same separation result is obtained. The recycling as describedin examples C1 and D2 may then be continued.

What is claimed is:
 1. A process for the preparation of2(S)-alkyl-5-halogenpent-4-ene carboxylic esters by enzymatichydrolysis, comprising the steps a) enzymatic hydrolysis of racemic2-alkyl-5-halogenpent-4-ene carboxylic esters in aqueous and alkalinemedium in the presence of an esterase; b) isolation of2(S)-alkyl-5-halogenpent-4-ene carboxylic esters by extraction with anorganic solvent; c) isolation of 2(R)-alkyl-5-halogenpent-4-enecarboxylic acids from the aqueous-alkaline medium; d) Esterification of2(R)-alkyl-5-halogenpent-4-ene carboxylic acids, e) subsequentracemization to form 2-alkyl-5-halogenpent-4-ene carboxylic esters; andf) return of the racemate obtained in step e) to step a), if necessarytogether with fresh racemic 2-alkyl-5-halogenpent-4-ene carboxylicesters.
 2. A process according to claim 1, comprising an embodimentwherein 2(S)-alkyl-5-halogenpent-4-ene carboxylic ester corresponds toformula I,

wherein R₁ is C₁-C₆alkyl, Z is c d the OR group forms an ester groupwith the carbonyl residu
 3. A process according to claim 1, comprisingan embodiment wherein the racemate used in process a) corresponds toformula II.

wherein R₁ is C₁-C₆alkyl, Z is chlorine, bromine or iodine, and the ORgroup forms an ester group with the carbonyl residue.
 4. A processaccording to claim 1, comprising an embodiment wherein2(S)-alkyl-5-halogenpent-4-ene carboxylic acid corresponds to formulaIII,

wherein R₁ is C₁-C₆alkyl and Z is chlorine, bromine or iodine.
 5. Aprocess according to claims 2 to 4, comprising an embodiment wherein Zis chlorine.
 6. A process according to claim 2 or 3, comprising anembodiment wherein R is C₁-C₁₈alkyl.
 7. A process according to claim 6,comprising an embodiment wherein the alkyl is methyl or ethyl
 8. Aprocess according to claims 2 to 4, comprising an embodiment wherein R₁is C₁-C₄alkyl, and Z is chlorine.
 9. A process according to claims 2 to4, comprising an embodiment wherein Z is chlorine, R₁ is i-propyl, and Ris methyl or ethyl.
 10. A process according to claim 1, comprising anembodiment wherein the enzymatic hydrolysis in process step a) isperformed with diluted, aqueous KOH or NaOH.
 11. A process according toclaim 1, comprising an embodiment wherein the isolation is performed bymeans of extraction with an organic solvent which is not miscible withwater.
 12. A process according to claim 1, comprising an embodimentwherein the 2(R)-alkyl-5-halogenpent-4-ene carboxylic acids are isolatedby extraction with an organic solvent, the reaction mixture beingacidified beforehand.
 13. A process according to claim 1, comprising anembodiment wherein the 2(R)-alkyl-5-halogenpent-4-ene carboxylic acid iseither esterified with an esterification agent, or the carboxylic acidis converted to the acyl halide before esterification.
 14. A processaccording to claim 1, comprising an embodiment wherein the racemizationfollowing the esterification after process step d) is performed in thesame reaction vessel without isolation of the2(R)-alkyl-5-halogenpent-4-ene carboxylic ester.
 15. A process accordingto claim 1, comprising an embodiment wherein the racemization isperformed in the presence of an alkali metal alcoholate at elevatedtemperatures.